抑制铁死亡可逆转伴有射血分数保留的心力衰竭的小鼠模型。
Inhibition of ferroptosis reverses heart failure with preserved ejection fraction in mice.
机构信息
Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, No 37 Wainan Guoxue Road, Sichuan, 610041, China.
Laboratory of Mitochondria and Metabolism, West China Hospital, Sichuan University, Sichuan, 610041, China.
出版信息
J Transl Med. 2024 Feb 24;22(1):199. doi: 10.1186/s12967-023-04734-y.
BACKGROUND
Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of heart failure cases. The molecular mechanisms by which HFpEF leads to impaired diastolic function of the heart have not been clarified, nor have the drugs that target the clinical symptoms of HFpEF patients.
METHODS
HFpEF chip data (GSE180065) was downloaded from the National Center for Biotechnology Information (NCBI) database. Differentially expressed genes (DEGs) were filtered by the limma package in R and processed for GO and KEGG pathway analyses. Then, ferroptosis-related genes in HFpEF were identified by taking the intersection between DEGs and ferroptosis-related genes. CytoHubba and MCODE were used to screen ferroptosis-related hub DEGs in the protein-protein interaction (PPI) network. Establishment of a mouse HFpEF model to validate the transcript levels of ferroptosis-related hub DEGs and ferroptosis-related phenotypes. Transcript levels of ferroptosis-related hub DEGs and HFpEF phenotypic changes in the hearts of HFpEF mice were further examined after the use of ferroptosis inhibitors.
RESULTS
GO and KEGG enrichment analyses suggested that the DEGs in HFpEF were significantly enriched in ferroptosis-related pathways. A total of 24 ferroptosis-related DEGs were identified between the ferroptosis gene dataset and the DEGs. The established PPI network was further analyzed by CytoHubba and MCODE modules, and 11 ferroptosis-related hub DEGs in HFpEF were obtained. In animal experiments, HFpEF mice showed significant abnormal activation of ferroptosis. The expression trends of the 11 hub DEGs associated with ferroptosis, except for Cdh1, were consistent with the results of the bioinformatics analysis. Inhibition of ferroptosis alters the transcript levels of 11 ferroptosis-related hub DEGs and ameliorates HFpEF phenotypes.
CONCLUSIONS
The present study contributes to a deeper understanding of the specific mechanisms by which ferroptosis is involved in the development of HFpEF and suggests that inhibition of ferroptosis may mitigate the progression of HFpEF. In addition, eleven hub genes were recognized as potential drug binding targets.
背景
射血分数保留型心力衰竭（HFpEF）约占心力衰竭病例的 50%。HFpEF 导致心脏舒张功能障碍的分子机制尚不清楚，也没有针对 HFpEF 患者临床症状的靶向药物。
方法
从美国国立生物技术信息中心（NCBI）数据库中下载 HFpEF 芯片数据（GSE180065）。使用 R 语言中的 limma 包筛选差异表达基因（DEGs），并进行 GO 和 KEGG 通路分析。然后，通过取 DEGs 和铁死亡相关基因的交集，鉴定 HFpEF 中的铁死亡相关基因。使用 CytoHubba 和 MCODE 从蛋白质-蛋白质相互作用（PPI）网络中筛选铁死亡相关的枢纽 DEGs。建立 HFpEF 小鼠模型，验证铁死亡相关枢纽 DEGs 的转录水平和铁死亡相关表型。进一步研究 HFpEF 小鼠心脏中的铁死亡相关枢纽 DEGs 转录水平和 HFpEF 表型变化，以及铁死亡抑制剂的使用。
结果
GO 和 KEGG 富集分析表明，HFpEF 中的 DEGs 显著富集在铁死亡相关通路中。在铁死亡基因数据集和 DEGs 之间共鉴定出 24 个铁死亡相关 DEGs。通过 CytoHubba 和 MCODE 模块进一步分析建立的 PPI 网络，获得了 11 个 HFpEF 中的铁死亡相关枢纽 DEGs。在动物实验中，HFpEF 小鼠表现出明显的铁死亡异常激活。与铁死亡相关的 11 个枢纽 DEGs 的表达趋势，除了 Cdh1 外，与生物信息学分析的结果一致。抑制铁死亡改变了 11 个铁死亡相关枢纽 DEGs 的转录水平，并改善了 HFpEF 表型。
结论
本研究有助于更深入地了解铁死亡参与 HFpEF 发生发展的具体机制，并表明抑制铁死亡可能减轻 HFpEF 的进展。此外，还鉴定出 11 个枢纽基因作为潜在的药物结合靶点。
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